Glucose Tolerance Test Research Articles

EVALUATION OF ANTI-DIABETIC ACTIVITY OF METHANOLIC EXTRACT FROM THE FRUIT PEEL OF ATALANTIA MONOPHYLLA (LINN.) IN ALLOXAN INDUCED DIABETIC MICE

Objective: Atlantia monophylla is an indigenous medicinal plant, with a folk reputation as hypoglycemic agent throughout India. Considerable research has shown that plants rich in flavonoids content with anti-oxidant potential are known to be bioactive for the management of diabetes mellitus (DM). In the present investigation, hypoglycemic activity of aqueous fruit peel extract of A. monophylla was evaluated using alloxan-induced hyperglycemic mice. Methods: Aqueous extract of the fruit peel of A. monophylla (AEAM) was subjected to preliminary phytochemical screening and acute oral toxicity study as per Organization for Economic Cooperation and Development guidelines 425. AEAM was evaluated for hypoglycemic activity, Alloxan induced DM in mice, oral glucose tolerance test in fasted mice. In vitro α- amylase inhibitory in albino mice method was employed for evaluation of hypoglycemic activity. Results: All of the mice in each group had their blood glucose levels measured both before and after the treatments on fasting animals. The extract was given at doses of 200 mg/kg and 400 mg/kg body weight, or 100 mg/kg body weight of the conventional antidiabetic medication Metformin. A glucometer was used to measure the blood glucose level. After 1 h, 2 h, and 4 h, the extract-treated diabetic mice had a substantial (p≤0.05) drop in blood glucose levels. The hypoglycemic action was similar to that of the medication Metformin used as a benchmark. Conclusion: The results of this study indicate that AEAM has strong hypoglycemic properties. One such method might include the activation of insulin receptors and subsequent release of insulin once β cells are stimulated. The hypoglycemic effect of the plant could be achieved through increasing insulin release from the pancreas.

Gestational Diabetes Mellitus and Risk Factors in a Multi-Ethnic National Case-Control Study.

Gestational diabetes mellitus (GDM) continues to increase particularly for non-European women. This study aimed to identify and quantify risk factors for women diagnosed with gestational diabetes in New Zealand to identify women at higher risk. A national dataset of 601,166 eligible women who had ≥ 1 birth in New Zealand between January 2001 and December 2010 identified 11,459 women with gestational diabetes of whom 11,447 were randomly matched with 57,235 control women for age and year of delivery. Adjusted odds ratios (95% CI) showed higher odds of gestational diabetes for Asian (3.60, 3.39-3.82), Pacific (2.76, 2.57-2.96) and Māori (1.23, 1.15-1.31) women compared with European/Other women. Women most economically disadvantaged (1.44, 1.34-1.56), not registered with a lead maternity carer (1.16, 1.04-1.30) and those identified as smokers (1.20, 1.11-1.31) were more likely than control women to develop gestational diabetes. In contrast, women residing in rural (0.83, 0.77-0.88) and remote areas (0.68, 0.60-0.77) were less likely to develop gestational diabetes compared with women living in urban areas, and similarly for non-New Zealand resident women (0.78, 0.72-0.85) compared with resident women. Women who were diagnosed with gestational diabetes were more likely to be non-European, economically disadvantaged, residing in urban areas, unregistered with a lead maternity carer and more likely to smoke. In addition to universal screening for pre-existing diabetes, all women at risk of gestational diabetes should be identified and supported to undertake to a 75 g glucose challenge test between 24 and 28 weeks.

Higher Serum Dipeptidyl Peptidase-4 Activity in Newly Diagnosed Young-Onset Type 2 Diabetes Mellitus.

Background Dipeptidyl peptidase-4 (DPP4) enzyme inhibition is a therapeutic modality for type 2 diabetes mellitus (T2DM). However, its activity is insufficiently explored yet in youth-onset T2DM. Objective The objective of this study is to measure serum DPP4 enzyme activities in youth-onset T2DM and compare them with those in patients with normal glucose tolerance (NGT). Methods This cross-sectional study comprised 29 young participants with newly diagnosed untreated T2DM (age 24.5±4.5 years, range 13-30 years, 51.7% female) and an equal number of young participants with NGT (age 26.5±2.9 years,48.3% female) screened by a two-sample 75gm oral glucose tolerance test. The relevant history of each participant was obtained, and the waist circumference, waist-hip ratio, blood pressure, and body mass index (BMI) were measured according to the standard procedure and recorded in the data collection sheet. Plasma glucose was measured using the glucose oxidase method, and serum DPP4 activity was measured using the colorimetry method. Results Participants with DM exhibited significantly higher serum DPP4 activity than NGT (DM vs. NGT: 481.4±70.4 pmol/min. vs. 420.3±49.2 pmol/min, mean±SD; p<0.001). A multivariate linear regression model adjusted for age, sex, BMI, and hypertension, found DM as an independent predictor for DPP4 activity (β=0.63.5, 95% CI 28.7-98.4, p=0.022). Conclusion DPP4 activity was significantly elevated in young participants with newly diagnosedT2DM. There might be a pathophysiological implication of DPP4 activity in young-onset T2DM.

6900 Fetal Abdominal Obesity in Women Exhibiting One Abnormal Value on Diagnostic Testing for Gestational Diabetes Mellitus

Abstract Disclosure: W. Kim: None. S. Park: None. Y. Kim: None. Background: Fetal abdominal obesity (FAO) was already observed at the time of diagnosis of GDM in our previous study. We investigated whether fetuses of women with hyperglycemia milder than GDM showed accelerated abdominal growth, leading to adverse pregnancy outcomes. Methods: We retrospectively reviewed the medical records of 7,569 singleton pregnant women who were universally screened using a 50-g glucose challenge test (GCT) and underwent a 3-h 100-g oral glucose tolerance test (OGTT) if GCT result was ≥140mg/dL. GDM, one value abnormality (OVA), and normal glucose tolerance (NGT, NGT1: GCT negative, NGT2: GCT positive &amp; OGTT negative) were diagnosed using Carpenter-Coustan criteria. With fetal biometry data measured simultaneously with 50-g GCT, relative fetal abdominal overgrowth was investigated by assessing the fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference(AC) per actual GA by the last menstruation period(LMP), biparietal diameter (BPD) or femur length(FL), respectively. FAO was defined as FAOR ≥90th percentile Results: The FAORs of GA-AC/GA-LMP and GA-AC/GA-BPD were significantly higher in OVA subjects compared to NGT subjects but not in NGT2 subjects. Although the frequency of FAO in OVA (12.1%) was between that of NGT (9.6%) and GDM (18.3%) without statistically significant difference, the prevalence of large for gestational age at birth and primary cesarean delivery rates were significantly higher in OVA (9.8% and 29.7%) than in NGT (5.1% and 21.5%, p&amp;lt;0.05). Particularly, among OVA subjects with FAO, the prevalence (33.3% and 66.7%) was significantly higher than in those without FAO (9.7% and 24.2%, p&amp;lt;0.05). Conclusion: The degree of fetal abdominal growth acceleration in OVA subjects was intermediate between that of NGT and GDM subjects. OVA subjects with FAO at the time of GDM diagnosis were strongly associated with adverse pregnancy outcomes. Presentation: 6/2/2024

FASTING BLOOD SUGAR (FBS) IN THE FIRST TRIMESTER: PREDICTIVE VALUE FOR GESTATIONAL DIABETES MELLITUS AND IMPACT ON PREGNANCY-RELATED OUTCOMES

Gestational diabetes mellitus (GDM) is a significant health concern in pregnancy, affecting maternal and neonatal outcomes. Early detection of GDM through fasting blood glucose (FBS) screening may help in timely management to prevent complications. Objective: To determine the fasting blood glucose threshold that accurately predicts the onset of gestational diabetes mellitus (GDM) and its impact on pregnancy outcomes. Methods: A prospective cohort study was conducted at the Obstetrics and Gynecology Department of Jinnah Postgraduate Medical Centre (JPMC), Karachi, from August 2023 to May 2024, involving 405 pregnant women selected through systematic random sampling. Inclusion criteria included singleton pregnancies, excluding women with pregestational diabetes or baseline fasting glucose levels of 126 mg/dL or higher. Baseline data on age, BMI, gestational age, and family history of diabetes were collected, and FBS levels were measured at the initial visit. Oral Glucose Tolerance Tests (OGTT) were conducted between 24 to 28 weeks of gestation to diagnose GDM. Maternal and fetal outcomes were monitored until delivery. Statistical analyses, including logistic regression and ROC curve analysis, were performed using IBM SPSS version 20. Results: Among the 405 participants, with a mean age of 28 ±6.49 years, the mean fasting blood sugar (FBS) was 89.5 mg/dL (±12.3). Impaired FBS (≥92 mg/dL) was noted in 24.70% of participants, and 18.27% were diagnosed with GDM following OGTT. A fasting glucose level of 127.4 mg/dL (±22.1) was observed among women diagnosed with GDM. Logistic regression showed a significant association between FBS ≥92 mg/dL and GDM risk (OR 1.08, CI 1.02-1.14, p=0.011). ROC analysis revealed an FBS cutoff of 92 mg/dL with 73% sensitivity and 68% specificity for predicting GDM. Gestational hypertension was observed in 8.64% of participants, and preeclampsia in 6.67%. Vaginal deliveries occurred in 72.1% of cases, while 27.9% required cesarean sections. Neonatal outcomes showed an 11% macrosomia rate, with 12% requiring NICU admission. Conclusion: Fasting blood glucose levels ≥92 mg/dL in early pregnancy are strongly predictive of gestational diabetes mellitus (GDM). Early FBS screening allows for timely intervention, potentially improving maternal and neonatal outcomes. This study underscores the importance of incorporating FBS screening in routine antenatal care for better pregnancy management.

8353 Impact of a plant-based protein diet on bone health and body composition in Sprague Dawley rats

Abstract Disclosure: M.M. Gomes: None. I.M. de Araújo: None. S.V. Rodriguez: None. F.R. Jorge: None. F.J. de Paula: None. Introduction:Vegetarian and vegan diets are associated with some health benefits; this has contributed to their growing popularity. Although studies remain limited, there is evidence that these patients may be at greater risk of reduced bone mineral density (BMD) and increased fracture risk. The general objective of this study was to analyze the impact of a high-protein, plant-based diet on bone tissue and body composition in male Sprague Dawley rats. Methodology: The study was approved by the Animal Ethics Committee. This study was done with 10 rats in the control group (CG), which received a standard AIN-93M diet; 11 in the normoprotein vegetarian group (NVG), with a normoprotein AIN-93 diet modified with pea protein and methionine; and 11 in the high-protein vegetarian group (HVG), with a modified AIN-93 diet with 40% pea protein and methionine. The dietary intervention lasted 8 weeks. The weight of the animals was measured weekly. Basal blood glucose levels were measured at baseline. At the end of the study, 6 rats from the CG, 6 rats from the NVG, and 5 rats from the HVG were subjected to a glucose tolerance test (GTT). The dual-energy X-ray absorptiometry (DXA) technique was applied in the baseline and final periods of the experiment to evaluate body composition, bone mineral content (BMC) and BMD. After sacrifice, bone strength was measured via a three-point flexion mechanical test on the tibia; brown adipose, epididymal, and retroperitoneal tissues, as well as the liver, were weighed on an analytical balance. Blood was used to measure circulatory levels of insulin, CTX, and P1NP (n=6/group). Results: Basal weight was similar between the groups, but the final weight was lower in the HVG as compared to the CG. In the DXA evaluation, the final lean mass was not different between the groups. On the other hand, total fat mass was lower in the HVG than in the CG and the NVG and the fat percentage was lower in the HVG than in the CG. The weight of epididymal adipose tissue was lower in the HVG than in the NVG, but retroperitoneal and brown adipose tissues were lower in HVG than CG. Liver weight was similar between groups. BMD was similar between groups; however, BMC was lower in the HVG than in the CG and the NVG. Bone strength was similar between groups. There was no difference in glycemia at baseline or during GTT at the eighth week. Serum levels of insulin, CTX, and P1NP were similar between groups. Discussion and Conclusion: A normoprotein vegetarian diet that includes all essential amino acids appears to have no negative impact on body composition or BMD in rats. On the other hand, a high-protein diet with plant protein appears to have a negative impact on bone mineral content, in addition to reducing the amount of body fat and weight. This finding expands on previous results by showing that high-protein diets have a negative impact on bone even when the protein is of plant origin. Presentation: 6/1/2024

6560 Atypical Diabetes Mellitus in a Mother-Son Pair with Multiple Autoimmune Conditions &amp; Pathogenic Variant in BCL11B Inherited from the Mother

Abstract Disclosure: R. Elrajabi: None. N. Gurtunca: None. The etiology of diabetes can be challenging to determine at times and misdiagnosis is common in all age groups. To provide the right treatment and enhance glycemic control, which results in better outcomes and fewer comorbidities, an accurate diagnosis is crucial. We describe a mother-son pair who share a pathogenic variant in BCL11B gene with multiple autoimmune conditions including atypical autoimmune DM. A 13 year old young boy with a history of 33-week prematurity, developmental delay, autoimmune hypothyroidism, and vitiligo presented with concerns for DM given mother’s recent diagnosis of DM treated with Metformin and GLP-1 receptor agonist with poor control of her DM. His mother has a learning disability, hypothyroidism, alopecia totalis, vitiligo and hypertension. Interestingly, he and his mother share a genetic variant in BCL11B gene detected on whole exome sequencing sent as part of the workup of developmental delay. His weight and height were in the 13.5% and 13.9% centiles, respectively. He has vitiligo, but other than that, the physical examination was unremarkable. He is prepubertal. HbA1c was high, 6.4% despite the presence of anemia. An oral glucose tolerance test (OGTT) was consistent with DM as was his repeat HbA1c of 7.1%. He had elevated IA 2, zinc transporter 8, and GAD 65 antibodies, all consistent with autoimmune DM. He was admitted to the hospital and started on both long-acting and short acting insulin via multiple daily injections. BCL11B is a transcription factor that is expressed in all T cells and regulates important processes involved in T cell growth, survival, and function, including Treg cells and Foxp3 activity. Autoimmune diseases have been linked to abnormal Treg activity and Foxp3 deficiency. BCL11B functions as a checkpoint required for T cell lineage commitment while minimizing natural killer cell potential. Impaired BCL11B activity at a young age result in severe whole-body autoimmunity, defined by a fully stimulated immune system similar to animals lacking functioning Treg cells. DM associated with BCL11B variant has not previously been reported. If we follow the theory that autoimmunity affects beta cell function or mass, this patient's and his mother's DM and autoimmune disorders are most likely connected to the BCL11B variation they share. Presentation: 6/2/2024

12395 Continuous Glucose Monitoring In Pseudohypoparathyroidism Type 1a

Abstract Disclosure: J. Tamaroff: None. A.E. Lee: None. A.H. Shoemaker: None. Background: Pseudohypoparathyroidism type 1A (PHP1A), due to heterozygous mutations in GNAS, is a rare disorder that leads to multi-hormone resistance, cognitive impairment, and early-onset obesity. Individuals with PHP1A have dysglycemia on oral glucose tolerance tests and increased rates of type 2 diabetes (T2DM). Individuals with rare diseases, like PHP1A, may travel significant distances for specialized clinical or research care. Wearable technology may alleviate barriers and provide useful information for clinical care or for use as potential biomarkers. The objective of this study is to evaluate glycemia in individuals with PHP1A and feasibility of utilizing continuous glucose monitors (CGMs) in this population. Methods: Observational study of individuals with PHP1A (3R01DK118407-03S1). CGMs (Dexcom Pro, Dexcom Inc, San Diego, CA) were placed on participants’ abdomens, typically by a family member, over secure-video call with study staff. CGMs collected data every 5 minutes for up to 10 days. Results: Seven participants (all female) with PHP1A without a diagnosis of diabetes had available data. Median age was 17 years (IQR: 14, 19; range: 8-23). Body mass index (BMI) categories (by percent of the 95th percentile for those under 18 years and BMI for adults) spanned from overweight to class 3 obesity. In terms of feasibility, 1 individual had to replace a CGM sensor due to an upcoming MRI and 1 individual had a “sensor failure” of unclear etiology. Both were able to place new CGMs. Individuals participated across 5 states in the United States. Median length of wear was 9.8 days (IQR 8.6, 9.9). Participants had a median average glucose of 104mg/dL (IQR 102, 111) and COV of 16% (15, 21). Percent of glucose &amp;gt; 140mg/dL was 5.0% (IQR: 1.8, 10.9; range:1.2-19.4%). One individual had 3.2% of glucose values ≥ 200mg/dL despite a normal hemoglobin A1c (HbA1c) level (5.5%). This level of hyperglycemia is qualitatively higher than published CGM data in healthy individuals. One study found individuals (6-24 years of age) had median percent of glucose values over 140mg/dL ranging from 1.2 to 2.4% with IQR values ranging from 0.3 to 4.4%, based on age categories.1Conclusions: In females with PHP1A, with overweight or obesity, CGM placement at home is a feasible way to collect real-world data. Participants with rare diseases often must travel for clinical and research care and CGMs may provide insight into glycemia without requiring an in-person visit. This “real-world” data mirrors research data reporting glycemia with normal HbA1c levels. The rate of hyperglycemia is higher than expected in some individuals with PHP1A though more data is needed. Ongoing studies will evaluate matched control participants and assess drivers of glycemia including inactivity and decreased sleep duration, as measured by actigraphy.

7789 PCOS and probiotics - a randomized controlled trial with a comparison to metformin

Abstract Disclosure: B.M. Obermayer-Pietsch: None. B. Valentin: None. B. Luegger: None. R. Regina: None. C.W. Haudum: None. V. Tandl: None. Polycystic ovary syndrome (PCOS) has a complex association not only with gonadal hormones, but also with insulin resistance and the gut – showing a decreased alpha diversity of the microbiome in PCOS women. Based on our previous investigations, we conducted a randomized controlled trial (RCT) using probiotics (OMNi-BiOTiC®, Institut Allergosan) and placebo daily, compared to a metformin group over 6 months. In this RCT, we included 112 women with PCOS, defined by Rotterdam criteria. Clinical and biochemical characterisation covered medical history with cycle abnormalities, Ferriman–Gallwey (FG) Score and anthropometric data. Hormonal profiles included gonadal hormones with a focus on androgens and AMH. Oral glucose tolerance tests (oGTT) with parallel insulin/c-peptide determinations and stool sampling for microbiome determination at every visit were done. Study participants were randomized 2:1 for probiotics/placebo or metformin (Glucophage®, Merck) and further 1:1 between probiotics and placebo for 6 months followed by a voluntary 6 months period on probiotics only. NGS for microbiome profiles was carried out. 93 PCOS women completed the study, 19 drop-outs for various reasons including 6 pregnancies were recorded (5 in the probiotic/placebo group, 1 in the metformin group). Participants were 27±5 years old, obesity with a BMI &amp;gt;30 was found in 35% of them. Initial cycle duration ranged from 22 to 200 days, 18% had amenorrhoea. Hirsutism was present with a mean FG score of 12,7±7,71. Mean levels (±standard deviation, reference range, no units depicted) for total testosterone were 0,38±0,15 (0,14-0,77), SHBG 54,1±29,0 (19–117), free testosterone 3,2±3,1 (0,45-2,19) and AMH 8,9±4,8 (0,17-7,37). Initial oGTTs showed insulin resistance prevalent in 43%, with an overall reduction to 36% at visit 2. Weight loss over 6 months was documented in 37%, cycle abnormalities decreased overall to 14%. Group comparisons and microbiome characterisation are ongoing. No serious adverse reactions related to the study medication were recorded. All intervention products were well tolerated in our PCOS study cohort. Based on the intended cycle normalisation, 6 pregnancies were recorded. Metabolic changes were seen both in the probiotic/placebo and in the metformin groups, with fewer changes in the placebo group despite nutritional counselling. Microbiome changes were recorded in both intervention groups. Presentation: 6/3/2024

The endocrine manifestations of adults with spinal muscular atrophy.

Changes in body composition in patients with spinal muscular atrophy (SMA) can cause endocrine abnormalities that are insufficiently studied in adults. We aimed to assess the endocrine profile in a cohort of adults with SMA. Second, we compared body composition and endocrine profiles between nonambulatory and ambulatory patients and between different types of SMA. The cross-sectional study included 29 SMA patients (18 [62.1%] males and 11 [37.9%] females) of median age 44 (IQR 30-51.5) years with type 2, 3, or 4. Body composition was measured by bioimpedance. Morning blood samples were drawn for glycated hemoglobin (HbA1c), lipid profile, testosterone, cortisol, and insulin-like growth factor-1 (IGF-1). Blood glucose, insulin, and beta-hydroxybutyrate (BHB) were measured during a 75 g oral glucose tolerance test. The homeostatic model assessment for insulin resistance index was calculated. In total, 75.9% of patients had increased fat mass (FM), with 51.7% having an increase despite normal body mass index. Ambulation was the most important discriminating factor of body composition. 93.1% of patients had metabolic abnormalities, including hyperglycemia, insulin resistance, and dyslipidemia. Increased BHB, a marker of ketosis, was present in more than a third of patients. Functional hypogonadism was present in half of male patients. Testosterone and IGF-1 negatively correlated with FM. Adult patients with SMA had abnormal body composition and highly prevalent metabolic disturbances that might increase cardiometabolic risk. Because treatments have modified the course of SMA, it is important to investigate whether these observations translate into clinically relevant outcomes.

7789 PCOS and probiotics - a randomized controlled trial with a comparison to metformin

Abstract Disclosure: B.M. Obermayer-Pietsch: None. B. Valentin: None. B. Luegger: None. R. Regina: None. C.W. Haudum: None. V. Tandl: None. Polycystic ovary syndrome (PCOS) has a complex association not only with gonadal hormones, but also with insulin resistance and the gut – showing a decreased alpha diversity of the microbiome in PCOS women. Based on our previous investigations, we conducted a randomized controlled trial (RCT) using probiotics (OMNi-BiOTiC®, Institut Allergosan) and placebo daily, compared to a metformin group over 6 months. In this RCT, we included 112 women with PCOS, defined by Rotterdam criteria. Clinical and biochemical characterisation covered medical history with cycle abnormalities, Ferriman–Gallwey (FG) Score and anthropometric data. Hormonal profiles included gonadal hormones with a focus on androgens and AMH. Oral glucose tolerance tests (oGTT) with parallel insulin/c-peptide determinations and stool sampling for microbiome determination at every visit were done. Study participants were randomized 2:1 for probiotics/placebo or metformin (Glucophage®, Merck) and further 1:1 between probiotics and placebo for 6 months followed by a voluntary 6 months period on probiotics only. NGS for microbiome profiles was carried out. 93 PCOS women completed the study, 19 drop-outs for various reasons including 6 pregnancies were recorded (5 in the probiotic/placebo group, 1 in the metformin group). Participants were 27±5 years old, obesity with a BMI &amp;gt;30 was found in 35% of them. Initial cycle duration ranged from 22 to 200 days, 18% had amenorrhoea. Hirsutism was present with a mean FG score of 12,7±7,71. Mean levels (±standard deviation, reference range, no units depicted) for total testosterone were 0,38±0,15 (0,14-0,77), SHBG 54,1±29,0 (19–117), free testosterone 3,2±3,1 (0,45-2,19) and AMH 8,9±4,8 (0,17-7,37). Initial oGTTs showed insulin resistance prevalent in 43%, with an overall reduction to 36% at visit 2. Weight loss over 6 months was documented in 37%, cycle abnormalities decreased overall to 14%. Group comparisons and microbiome characterisation are ongoing. No serious adverse reactions related to the study medication were recorded. All intervention products were well tolerated in our PCOS study cohort. Based on the intended cycle normalisation, 6 pregnancies were recorded. Metabolic changes were seen both in the probiotic/placebo and in the metformin groups, with fewer changes in the placebo group despite nutritional counselling. Microbiome changes were recorded in both intervention groups. Presentation: 6/3/2024

8780 The Role of Nuclear Receptor Corepressors 1 and 2 on Intestinal Carbohydrate Transport in Mice

Abstract Disclosure: M.J. Ritter: None. I. Amano: None. A.H. van der Spek: None. H.E. Daniel: None. A.N. Hollenberg: None. The nuclear receptor corepressors NCoR1 and NCoR2 are two critical regulators of metabolism that are required for maintaining metabolic homeostasis. Both NCoR1 and NCoR2 (also known as the silencing mediator of retinoic acid and thyroid hormone receptors; SMRT) recruit histone deacetylase 3 (HDAC3) to their deacetylase domain (DAD) to repress nuclear receptor (NR) target gene expression. Interruption of the DAD of NCoR1 in mice leads to lower body weight, decreased whole-body fat mass, insulin sensitization with altered oscillatory patterns of key metabolic genes (1). On the other hand, total body knock-out (KO) of SMRT leads to weight gain, insulin resistance, and hepatic steatosis with an increase in hepatic lipogenesis (2). Previously, we showed that the KO of NCoR1 and SMRT in tandem from adult mice led rapidly to weight loss, hypoglycemia, hypothermia and was lethal. Reductions in intestinal carbohydrate transporters were seen, including sodium-glucose linked transporter-1 (SGLT1), glucose transporter 2 (GLUT2), and glucose transporter 5 (GLUT5) (3). Thus, we hypothesized that NCoR1 and SMRT play unique roles in regulating intestinal carbohydrate metabolism, in turn controlling metabolic parameters including body mass and glucose levels. We then generated a novel model to enable KO of NCoR1 and SMRT throughout intestinal epithelial cells (IECs) in adult mice using a tamoxifen inducible cre under control of the villin 1 promoter. Mice were injected with tamoxifen and body weight and glucose were monitored daily. This was followed by both oral and intraperitoneal glucose tolerance testing (GTT) and metabolic phenotyping. Preliminary data showed that NCoR1 and SMRT KO leads to sustained weight loss and hypoglycemia with 50% survivability. Metabolic phenotyping confirmed reduction in body mass without concomitant reduction in food intake. Oral GTT showed a blunted peak in response to glucose gavage compared to intraperitoneal administration. Gene expression analysis showed reduction in SGLT1, GLUT2, and GLUT5 in addition to changes in metabolic pathways associated with fatty acid metabolism. Here, we show that NCoR1 and SMRT are critical regulators of body mass and glucose in part via their actions on carbohydrate transporters in the intestine. With the global burden of metabolic diseases, including obesity and diabetes, ever-rising, NCoR1 and SMRT represent an overlooked but important area of study to better our understanding of disease processes and identify new targets for treatment. We next aim to determine the functional mechanism by which weight loss and hypoglycemia develop in addition to identifying molecular targets and pathways regulated by NCoR1 and SMRT in IECs.

7718 Dysregulated BCAA catabolism and insulin secretory response in the early stages of insulin resistance in mature adolescents

Abstract Disclosure: A. Basin: None. Q. Wang: None. H. Hong: None. O. Ilkayeva: None. M. Muehlbauer: None. D. Hsia: None. D.A. D'Alessio: None. C.B. Newgard: None. M. Freemark: None. P. Gumus Balikcioglu: None. Objective: We recently showed that surrogate markers of insulin resistance (IR) and insulin secretion are differentially associated with branched-chain amino acids (BCAAs) and their catabolites the branched-chain ketoacids (BCKAs). In this longitudinal study, we determined if baseline levels of BCAAs, BCKAs or the BCKA/BCAA ratio are associated with changes in IR, insulin secretion, and insulin secretion adjusted for IR after a one year follow up in adolescents aged 18-21 yr without Type 2 diabetes. Methods: We performed frequently sampled oral glucose tolerance tests (OGTT) at baseline and one year follow up in 10 adolescents with normal weight and 10 adolescents without Type 2 diabetes but with overweight/obesity and mild IR. After an overnight fast of 8-12 hours, participants had fasting blood samples drawn and consumed 1.75 g/kg, to a maximum of 75 g glucose solution as the initiation of an OGTT. Glucose (G) and insulin (I) were measured at times -15, 0, 10, 15, 30, 45, 60, 90, 120, and 180 minutes. Plasma metabolomic profiles were obtained at time 0. HOMA-IR, Matsuda Index, AUC glucose, AUC insulin, insulinogenic index (IGI) and disposition index (DI) at 15 and 30 min were calculated. % Body fat was measured by TANITA. Results: At one year follow up groups were comparable in age, sex, race, ethnicity and pubertal status. Participants with overweight/obesity had higher BMI (22.5±1.3 vs 36.2±9.7), BF% (16.8±8.4 vs 37.9±10.2), leptin, and diastolic blood pressure than lean participants. They were also more insulin resistant as evidenced by higher HOMA-IR . AUC glucose,AUC insulin, and IGI were comparable across groups, as were fasting BCAA levels and BCKA/BCAA ratio. As with baseline levels, follow-up BCAA levels correlated positively with AUC insulin, HOMA-IR, and IGI at 30 min and negatively with totaland HMW-adiponectin, and Matsuda Index, but did not correlate with BMI or % body fat. Likewise at follow up, BCKAs correlated negatively with total and HMW-adiponectin and did not correlate with Matsuda Index, or HOMA-IR. In association models adjusted for baseline age, sex, and BMI, higher baseline levels of the BCKA, α-keto-β-methylvalerate (KMV, isoleucine catabolite), and a higher BCKA/BCAA ratio were associated with a relative reduction in acute insulin secretion as reflected in a reduction in 15 min IGI at 1 year follow up. Conclusions: In this cohort of adolescents without Type 2 diabetes and with varying degrees of adiposity and insulin sensitivity, we identified KMV as a marker associated with a subsequent reduction in acute glucose-stimulated insulin secretion at one year follow up.These findings suggest that dysregulated BCAA catabolism is associated with loss of compensatory insulin secretion in the face of IR and may play a role in progression to impaired glucose tolerance and development of Type 2 diabetes. Presentation: 6/1/2024

7252 Difference between interstitial and blood glucose during glucose loading is associated with the degree of insulin resistance in subjects with prediabetes and type 2 diabetes

Abstract Disclosure: D. Kim: None. S. Ryang: None. M. Im: None. J. Kim: None. Y. Kim: None. Y. kim: None. J. ha: None. J. Kim: None. S. Kim: None. Background and Aims: This study investigated the main factors responsible for the differences between blood glucose (BG) and interstitial fluid glucose (ISF) during glucose loading. Methods: A total of 204 Korean subjects without history of type 2 diabetes were enrolled. The subjects were categorized into three groups according to diabetes criteria by American Diabetes Association; NGT (normal glucose tolerance, n=36), PreDM (prediabetes, n=130) and T2D (undiagnosed type 2 diabetes, n=38). For glucose monitoring, a CGM (continuous glucose monitoring) system (Dexcom G6, Dexcom, San Diego, USA) was attached for 10 days. 75g oral glucose tolerance test (OGTT) was performed during applying CGM with stabilization (after wear of 3 days). Blood sample collected at t=0, 30, 60, 90 and 120 min for glucose and insulin concentration. Two parameters [insulin sensitivity (mIS) and beta-cell function (mBCF)] were derived novel mathematical model. Results: Among NGT, PreDM and T2D, there are heterogeneity in the difference and pattern between BG and ISF in this study. We identified the probability density function of BG - ISF across glucose tolerance, there is a trend that the means of BG - ISF with G60, 90, and 120 move to the right, as glucose tolerance status changes NGT to PreDM and DM. BG - ISF is significantly associated with insulin resistance (R=0.32, p&amp;lt;0.001), not diminished beta cell function. Conclusions: Because individuals vary in their degree of insulin resistance as a primary pathophysiology of type 2 diabetes, the caution should be needed in interpreting the glycemic response of CGM after a glucose load. Presentation: 6/3/2024

Associations of the rs12504538 and rs6824447 Polymorphisms of the Elovl6 Gene with Estimated Elongase and Desaturase Activity and Fatty Acid Concentrations in Mexican Women with Gestational Diabetes Mellitus

Background: This study aimed to investigate the possible associations of the rs12504538 and rs6824447 polymorphisms of the Elovl6 gene with estimated elongase and desaturase activity and saturated fatty acid concentrations in Mexican women with Gestational Diabetes Mellitus (GDM). Methods: We recruited 172 women in the second and third trimesters of pregnancy who had undergone an oral glucose tolerance test, including 66 who had diagnosed with GDM according to the 2016 ADA criteria and 106 who had normal glucose tolerance test results, from the General Hospital and Health Centers of the Health Ministry of Guanajuato, México. Participants were matched by gestational week. Data on age, gestational week and anthropometric characteristics were collected. Blood samples were drawn after an overnight fast for the measurement of serum glucose, lipid, NEFA, serum fatty acid and insulin levels; SNP genotyping and quantification of fatty acids was performed and elongase and desaturase activity was estimated. Findings: With the exception of HDL-cholesterol, all variables, including NEFA levels, were significantly greater in the GDM group than in the non-GDM group. The rs6824447 polymorphism of the Elovl6 gene, an age &gt;25 years and HOMA-IR levels were associated with the development of GDM (OR=5.1, 95% CI 1.56-17.1, p=0.006; OR=4.89, 95% CI 1.65-14.4, p=0.003; OR=34.1 95% CI 8.7-133, p&lt;0.000001, respectively). Palmitic acid (OR=1.08; 95% CI: 1.06-1.11; p&lt;0.001) and oleic acid (OR=1.17; 95% CI: 1.14-1.2; p&lt;0.001) concentrations were also associated with the development of GDM. No differences in the estimated elongase and desaturase activity among the non-GDM and GDM groups were found and only the activity of Δ9D SCD18 desaturase was marginally high in GDM patients (p=0.050). Conclusion: The rs6824447Elovl6 polymorphism is associated with the development of GDM, as are high serum palmitic acid, oleic acid and stearic acid concentrations and estimated Δ9D SCD18 desaturase activity.

12560 RIMOC1, A Novel Regulator Of Mitochondrial Function, And Its Role In Pancreatic Beta-cell Survival, Mitophagy, And Diabetogenesis

Abstract Disclosure: D. Filingeri: None. R. Liu: None. V. Negi: None. J. Lee: None. A. Kumar: None. V. Mandi: None. M. Moulik: None. V. Yechoor: None. Background: Literature supports preserving beta-cell function as an approach to slowing diabetes progression. Mitochondria emerge as an interesting area of focus, driving cellular respiration and glucose-stimulated insulin secretion (GSIS) within beta-cells in physiologic conditions, and leading to increased intracellular ROS generation when damaged. Damaged mitochondria are recycled via lysosomes by mitophagy, and defects in mitophagy have been linked to numerous disease states, with more recent data implicating impaired mitophagy with beta-cell death. Our previous work on the Hippo-TEAD pathway and beta-cell survival led to the isolation of the TEAD binding partner RIMOC1 (RAB7A-Interacting MON1-CCZ1 Complex Subunit 1), a protein highly expressed in pancreatic beta-cells, though its role in beta-cells remains unknown. The overarching hypothesis is that RIMOC1 is protective against the development of diabetes by preserving beta-cell mitophagy and mitochondrial function, and that impaired RIMOC1 function would lead to beta-cell failure and diabetes.Methods: We have generated both a stable INS2 RIMOC1 KO (knockout) cell line and an INS1-Cre RIMOC1 KO mouse model, that are beta-cell specific knockouts of RIMOC1. Mitochondrial membrane potentials were measured using TMRE and JC1 stains, and mitophagy was quantified using the mtKeima probe via flow cytometry. Protein expression was quantified via western blotting. Ongoing studies involving our mouse model include in vivo GTTs (glucose tolerance testing), ex vitro GSIS experiments to assess beta-cell function from mouse islets, and seahorse assays to quantify mitochondrial function. Results: Published GEO datasets show RIMOC1 expression is positively correlated with beta-cell maturity and negatively correlated with glucose load and HgbA1c. Our in vitro data demonstrates RIMOC1 knockout leads to decreased insulin mRNA expression, decreased insulin content, and increased beta-cell cycle inhibition. Early in vivo data shows worsened hyperglycemia with oral refeeding after fasting. In vitro mitophagy experiments demonstrate significantly diminished mitochondrial membrane potential in RIMOC1 KO INS2 cells. Conclusions: RIMOC1 is highly expressed in beta-cells and has a significant role in maintaining euglycemia through mitochondrial functioning, insulin processing, and altered mitophagy. This research highlights RIMOC1 as a promising target of further diabetes research. Presentation: 6/2/2024

12527 Determining The Impact Of Dampened Oxidative Stress On Islet Function And Gene Expression During Diabetes Onset In NOD Mice

Abstract Disclosure: K.V. Coutinho: None. H. Shinde: None. J. Feduska: None. K. Burnette: None. S.O. Poole: None. H.M. Tse: None. C.S. Hunter: None. Type 1 diabetes (T1D) arises from autoimmune destruction of insulin-producing pancreatic β-cells. Revealing the mechanisms underlying T1D onset are critical for therapeutic development but not completely understood. NADPH oxidase (NOX) generates superoxide, a precursor of reactive oxygen species (ROS), to regulate cell survival, differentiation, signaling, and autoimmune responses in T1D. NOD (Non-Obese Diabetic) mice spontaneously develop T1D, featuring increased cytokine/chemokine synthesis, inflammatory responsive macrophages and T cells, and ROS. Here, we harness NOD mice deficient in NOX-derived superoxide (NOD.Ncf1m[1]J), which have significantly lower T1D incidence. However, the impacts on islet β-cells in this T1D resistant model are unknown. We assessed a time course of glucose homeostasis between 6-20 weeks (W), spanning the onset T1D in NOD mice. Surprisingly, comparative glucose tolerance testing (GTT) in NOD.Ncf1m[1]J mice revealed increased glucose intolerance at 10W with no differences at 6, 14, and 20W as compared to NOD. Insulin tolerance was similar between the two models at all stages examined. This suggests superoxide production is necessary for β-cell function, despite that NOD.Ncf1m[1]J mice are T1D resistant. To understand islet transcriptomic changes between NOD and NOD.Ncf1m[1]J mice, we conducted comparative bulk islet RNA sequencing from 6 to 20W. Principal component analysis was applied to ensure differences between genotypes at each timepoint. Quality control methods within the Nextflow core pipeline were used to ensure sample quality. As expected, NOD.Ncf1m[1]J mice had decreased Ncf1 and immune response-related mRNA levels. Expression of T-cell exhaustion (Pdcd1, Lag3, and Tigit) genes remained level in NOD mice, but had significantly lower expression at 6W in NOD.Ncf1m[1]J mice. Interestingly, Ctla4, encoding a gene product that inhibits T-cell function, was upregulated at 14W in NOD.Ncf1m[1]J mice. Furthermore, GO analysis of downregulated NOD.Ncf1m[1]J gene sets include T-cell activation, response to IFN-β and IFN-γ at 6W, and decreased cytokine production at 20W. Supporting the dysregulation of β-cell function, Bace2, encoding a protease that limits β-cell function and mass, was upregulated with NOD. Ncf1m[1]J. Additionally, 14W β-cell function gene expression was decreased in the NOD.Ncf1m[1]J mice, including Slc2a2, which encodes the β-cell GLUT2 glucose transporter, and Glp1r, which is involved in preserving β-cell mass and function. Taken together, NOX-derived superoxide, whose loss decreases T1D incidence, may also dampen β-cell gene expression and function. Future directions will include comparative NOD and NOD.Ncf1m[1]J single cell transcriptomics to determine cell type specific transcriptional signatures between islet and immune cell subtypes. Presentation: 6/2/2024

7216 Absence Of Weight Gain In C57Bl/67 Female Mice On A High-Fat Diet Protects The Skeleton From Bone Loss

Abstract Disclosure: C. McAndrews: None. C. Chlebek: None. S. Costa: None. C.J. Rosen: None. Background: Obesity is associated with both systemic metabolic changes that increase the risk of comorbidities and reduced bone quality that increases the risk of fracture. The effects of high-fat diet consumption have been well studied in preclinical models where high-fat diet-feeding induces obesity, but there have been no studies to investigate the effects of high-fat diet-feeding in animals that do not become obese. Therefore, we characterized components of systemic metabolism and bone mineral content in non-obese C57Bl/6J mice that were fed a high-fat diet. Methods: Female C57Bl/6J mice aged 8 weeks received either a high-fat (60% kcal fat, n = 31) or control (10% kcal fat, n = 17) diet for 12 weeks. Body composition, areal bone mineral density (BMD) and bone mineral composition (BMC) were assessed after the feeding period using dual energy x-ray absorptiometry (Faxitron UltraFocus-DXA). Glucose (GTT) and insulin (ITT) tolerance testing were performed at the conclusion of the study. Changes in body weight were calculated as the difference between baseline and experiment end. High-fat diet-fed animals were classified as obese (HFD-O, n = 24) if they weighed more than 25 g or had greater than 25% body fat as evaluated via DXA, and were otherwise considered non-obese (HFD-NO, n = 7). In a small subset of animals, subcutaneous inguinal fat pads were harvested and weighed (n=5-7/group). Differences between groups were assessed with one-way ANOVAs and Tukey post-hoc analyses. Results: HFD-O mice weighed more than HFD-NO and control animals, whereas the body weights of HFD-NO mice were not significantly different from control (p &amp;lt; 0.001). Fat percent was increased in HFD-O mice compared to HFD-NO and control animals (p &amp;lt; 0.001). Subcutaneous inguinal fat mass was increased in both HFD-O and HFD-NO mice compared to control (p &amp;lt; 0.001). Fasting blood glucose did not significantly differ between groups. Glucose tolerance was worsened in both HFD-O and HFD-NO mice compared to control (p &amp;lt; 0.001), but there were no significant differences in insulin tolerance between groups. BMD was decreased in HFD-O mice compared to HFD-NO and control animals (p &amp;lt; 0.001). DISCUSSION: The consumption of a high-fat diet in mice induces deleterious metabolic changes irrespective of weight gain. However, high-fat diet-induced bone loss does not occur in the absence of weight gain. These findings suggest that certain adipokines derived from larger adipose depots may drive high-fat diet-induced bone loss and warrant further investigation. Acknowledgements: This work was supported by the 2023 Endocrine Society Research Experiences for Graduate and Medical Students (REGMS) Program. Presentation: 6/1/2024

7303 Fasting and Post-load Glucose in Exclusively Breastfeeding Women With Diabetes Risk Factors

Abstract Disclosure: N. Neamonitaki: None. T. Thaweethai: None. D. Pant: None. K. James: None. M.D. Soffer: None. E.A. Rosenberg: None. C.E. Powe: Consulting Fee; Self; Mediflix, Inc. Other; Self; Wolters Kluwer, Up to Date Author. Background: Epidemiologic studies show a reduction in type 2 diabetes incidence with increased lactation duration and intensity, but physiologic mechanisms underlying this association are incompletely characterized. We examined associations between lactation and glycemic physiology in postpartum women. ​ Methods: We conducted a secondary analysis of postpartum participants in a prospective longitudinal cohort study that examined glucose and insulin physiology via serial 2-hr 75-gram oral glucose tolerance tests during pregnancy and postpartum in women with diabetes risk factors. We used linear regression to examine associations between exclusive breastfeeding and fasting glucose, adjusting for age, race/ethnicity, education, body mass index, and number of weeks postpartum. Secondary analyses examined associations with post-load glucose and insulin physiology. Additional analyses considered exclusive breastfeeding compared to exclusive formula feeding and a combination of formula and breastfeeding separately using a categorical exposure variable. Results: Of N=108 women at a mean (SD) of 11 (5.0) weeks postpartum, 56 reported exclusively breastfeeding and 52 reported not exclusively breastfeeding (15 were exclusively formula feeding and 37 were both breast- and formula feeding). Mean (SD) fasting glucose was 83 (7.0) mg/dl in those exclusively breastfeeding and 85 (8.9) mg/dl in those who were not. Fasting glucose was not significantly different in those who were exclusively breastfeeding compared to those who were not after confounder adjustment (β [95% CI] =-1.3 [-4.6, 2.0] mg/dl, P=0.45). The 60- minute post-load glucose was nominally higher in those exclusively breastfeeding, with a mean (SD) of 132 (37.5) mg/dl versus 118 (31.6) mg/dl in those who were not; this difference did not reach statistical significance in the adjusted model (β [95% CI] =12.6 [-2.1, 27] mg/dl, P=0.09). In additional analyses, fasting glucose was not significantly different between women exclusively breastfeeding, exclusively formula feeding, or both breast- and formula feeding; however, post-load glucose at 30 and 60 minutes was higher in the exclusively breastfeeding group compared to the exclusively formula feeding group (30-minute: β [95% CI]= 16 [0.36,32] mg/dl, P=0.045); 60-minute: 26 [4.0,47] mg/dl, P=0.02) in adjusted models. We did not find significant associations with insulin physiology measures. Conclusion: We did not observe lower fasting glucose with exclusive breastfeeding. Instead, glucose levels at 30 and 60 minutes after an oral glucose load were higher in exclusively breastfeeding participants compared to exclusively formula feeding participants. Presentation: 6/2/2024

8413 Skeletal Muscle Mass, Insulin Sensitivity, And Beta-Cell Function In The Development Of Type 2 Diabetes: A 16-Year Prospective Cohort Study

Abstract Disclosure: H. Mun: None. S. Lee: None. S. Kim: None. S. Yoo: None. J. Son: None. Background: The relationship of relative muscle mass with beta-cell dysfunction and insulin resistance in the development of type 2 diabetes is unclear. We therefore aimed to evaluate longitudinal changes in glycemia, insulin sensitivity, and beta-cell function according to muscle mass. Methods: We prospectively evaluated 7090 middle-aged and older participants without diabetes at baseline every 2 years with oral glucose tolerance tests for 16 years in the Korean Genome Epidemiology Study. Weight-adjusted appendicular skeletal muscle mass was used to derive the muscle mass index (MMI). Using linear mixed-effect models, we assessed trajectories of fasting and 2-hour post-load glucose (2hPG), the composite insulin sensitivity index (ISIcomp), the 60-minute insulinogenic index (IGI60), and the disposition index (DI) according to sex-specific MMI tertiles before diagnosis with type 2 diabetes or the completion of follow-up. Results: During a median follow-up of 13.9 years, 1742 (24.5%) participants were diagnosed with type 2 diabetes. The risk of developing type 2 diabetes gradually increased as MMI decreased (multivariable-adjusted hazard ratio 1.36; 95% CI 1.29; 1.44 per SD decline in MMI). After age- and sex adjustment, significant differences were found in fasting and 2hPG trajectories between low and high MMI tertiles during follow-up (p &amp;lt; 0.001 for group-by-time interaction). The low MMI tertile showed significantly lower ISIcomp and DI at baseline compared to the high MMI tertile. The rate of increase in IGI60 was significantly lower in the low MMI tertile than in the high MMI tertile (0.0021 vs. 0.0191; p &amp;lt; 0.001) despite a progressive decline in ISIcomp during follow-up. The rate of decrease in DI was significantly greater in the low MMI tertile than in the high MMI tertile (-0.0228 vs. -0.006; p &amp;lt; 0.001). Conclusion: Sufficient muscle mass in middle-aged and older adults could protect against incident type 2 diabetes by preserving beta-cell function to compensate for aging-induced reductions in insulin action, independent of obesity. Presentation: 6/1/2024